Monoclonal antibodies are proving to be powerful therapeutic agents in the treatment of cancer owing to the selective targeting of antigens which are differentially expressed on cancer cells. The therapeutic strategies of most currently developed monoclonal antibodies include the targeting of tumor-associated antigens to modify tumor-cell biology, inhibition of growth factor receptors, inhibition of angiogenesis, apoptosis induction and cytotoxicity via complement fixation or antibody-dependent cellular cytotoxicity. Some antibodies target the growth factor receptors that are crucial for cancer cell survival, such as trastuzumab (Herceptin®) and cetuximab (Erbitux®). Targeting of the TRAIL death receptors on cancer cells with agonistic monoclonal antibodies represents a new generation of monoclonal antibody therapy, as they are able to directly induce apoptosis of targeted cells. The use of an agonistic monoclonal antibody against the death receptors instead of TRAIL may be advantageous: TRAIL targets multiple receptors including both the death receptors and decoy receptors and, therefore, selectivity is a concern. In addition, TRAIL has a much shorter blood half-life compared with monoclonal antibodies, a factor which affects dose and schedule parameters. The very short blood half-life of TRAIL would require large and frequent doses compared with monoclonal antibodies. In addition recombinant TRAIL is very difficult and tedious to produce.
Michaelson J. S. et al. (mAbs, Vol 1, Issue 2, p:128-141; March/April 2009) describe engineered IgG like biscpecific antibodies targeting two TNF family member receptors, namely TRAIL-R2 (TNF related Apoptosis Inducing Ligand Receptor-2) and LTβR (Lymphotoxin-beta Receptor).
Herrmann T. et al. (Cancer Res 2008; 68: (4); p: 1221-1227) describe bispecific monovalent chemically combined Fab molecules directed to CD95/Fas/Apo-1 cell surface receptor and three target antigens on glioblastoma cells: NG2, EGFR and CD40.